thoracic neuroendocrine tumours - oncologypro

Thoracic Neuroendocrine Tumours

Denis Talbot

Professor of Cancer Medicine, University of Oxford

3rd ESO-ESMO-RCE Clinical Update on Rare Adult Solid Cancers

Milan, 1st – 3rd December 2018Do not duplicate or d

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Goals of the Session

Presentation and Diagnosis

• Demographics

• Pathology

• Clinical Features

• Imaging and Staging

Management

• Surgery

• Somatostatin Analogues

• Peptide Receptor Radiotherapy

• Cytotoxic chemotherapy

• mTOR inhibitors

• Symptom management

• Future Horizons

Denis Talbot ESO 2018

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Incidence

Yao, J. Clin. Oncol, (2008)

Incidence of all malignant neoplasmsIncidence of NETs



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25%

16%

13%11%

9%

7%

6%

5%4% 4%

Primary Sites

Pulmonary Small Intestine Appendix Pancreas Skin

Colon/Caecum Stomach Rectum Bladder Oesophagus

Incidence of NETs, 2013-2015

Source: Public Health England

Number of Cases15,434

Age Standardized Incidence Rate8.7 per 100,000 per year (95% CI 8.6-8.8)


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Survival of Pulmonary NET and Lung Cancer diagnosed 2013-2015

Survival 5yr 10yrTC >90% >90%AC 70% 50%

LCNEC 15% 7%

SCLCC 3% 1%

Denis Talbot ESO 2018 Source: Public Health England


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Clinical Presentation

• Often asymptomatic and identified incidentally

• Respiratory Symptoms

Cough/chest pain/dyspnoea/haemoptysis/wheeze/recurrent infections

• Family history of MEN1

• Association with Syndromes in 2-5% cases• Carcinoid Syndrome commonly associated with hepatic metastases

• Ectopic ACTH: 40% of cases occur in thoracic NETs

• SIADH in up to 10% of SCLC

• Insulin hyper-secretion

• Ectopic GHRH or IGF-1: Acromegaly



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Bronchial Tumours: Initial Investigations



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Histological Classification

WHO 2015

Morphology Glandular, Spindle, Nestedor Plasmacytoid

Glandular, Spindle, Nestedor Plasmacytoid

NE morphologyCGA/SYN +

NE morphology

Cytological FeaturesCell size

Course chromatin

Course chromatin

Finely granular chromatin

Small cell, scant cytoplasm

Necrosis No No, focal or punctate

Yes Yes

Mitoses / 2 mm2 <2 2-10 >10Median 70

>10Median 80

Ki67 Up to 5% Up to 20% 40-80% 50-100%

Typical Carcinoid>0.5mm

Atypical Carcinoid Large Cell NEC Small Cell NEC


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DIPNECH and Tumourlets


Adrienne Am J Resp Crit Care, 2011

Diffuse Idiopathic Pulmonary Neuroendocrine Cell HyperplasiaHistology• Linear proliferation of scattered NE cells (pre-malignant)• Usually confined to bronchial epithelium• May extend beyond basement membrane to form Tumourlets

Clinical Features• F:M 10:1• Median age at presentation 58y• Not associated with smoking• Asymptomatic or symptoms of airflow obstructionDo not duplica

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Biochemical Markers

Chromogranin ARaised in• 75% bronchial carcinoids• 60% SCLC

NSEMay be raised in high grade pulmonary NETs

Screening for MEN-1<5% of pulmonary NETs• Serum Ca++

• PTH

Depending on symptoms• Urinary 5-HIAA• Plasma and urinary cortisol• ACTH• IGF-1

Modlin, Annals of Surg. Oncol. 2010 Denis Talbot ESO 2018


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Imaging of Pulmonary NETs

CT: Initial imaging for pulmonary lesions

Somatostatin Receptor Scintigraphy (SRS)• 111Indium pentetreotide

PET imaging• 68Ga-DOTA (DOTATOC or DOTATATE) PET• 18F-FDG PET/CT: Staging of tumours with high Ki67 (>10%)

MRI: Limited roleDenis Talbot ESO 2018


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Radionuclide Imaging and Therapeutics


Components• 68Gallium = Radionuclide• DOTATATE = Chelator for 68Ga• Tyr3 octreotate = binds to SSR

68Ga-DOTATATE

PRRT


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FDG and 68Gallium PET imaging

FDG PET 68Ga-DOTATATE PET/CT CT

Fused 68Ga PET / CT

Lung India 2012; 29(4): 378–380 Denis Talbot ESO 2018

Fused FDG PET/ CT


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Staging

Lymph Node Involvement and Stage Distribution1440 cases evaluated by ESTS NETs WG

Typical Carcinoid Atypical Carcinoid

Pulmonary Carcinoid Tumours

Survival according to Tumour Stage

Filosso, J Thoracic Dis. (2015)Denis Talbot ESO 2018


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https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4419025/figure/f4/

Left lower lobe Typical Carcinoid Tumour resected 1 year previously68Ga-DOTATATE PET/CT: local recurrence near surgical clips, regional sub-cm nodes and bony metastases

Courtesy of Michael HofmanPeter MacCallum Cancer Centre


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Treatment


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1970’s 1980’s 1990’s 2011 2015 2016 2017

Therapies for NETs: Historical PerspectiveFDA/EMA Approved

Not FDA/EMA Approved

STZ in pNET

Octreotide, IFN inCarcinoid Syndrome

Lanreotidein GEP NETS

Telotristat inrefractory

CS diarrhoea

Liver-directed:TACE/TAE/TARE

Pasireotide

Oxaliplatin

Octreotidein mid gut NETs

PRRT in GEP NET

Everolimus in non functioning NETs

Sunitinib, Everolimusin pNET

Lanreotide inCarcinoid Syndrome

Bevacizumab

Etoposide/ PtSCLC

Cytotoxic Agents

Treatment of CS

Signaling Pathways

Radiation / Physical

SSA as anti-tumour agentsDo not duplica

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Pulmonary Neuroendocrine Tumours:Treatment Options

• Surgery

• Targeted therapy• Everolimus (mTOR)

• Peptide Receptor Radionuclide Therapy (PRRT)

• Cytotoxic chemotherapy• Platinum Etoposide (SCLC)• Temozolomide/Capecitabine

• Somatostatin Analogues

• Tryptophan Hydroxylase Inhibitors (Telotristat)

• IFN-2Alpha

• Embolization/SIRT

Factors Determining Optimal TherapyPathologyProliferation• Mitotic Index• Ki67

Somatostatin Receptor ExpressionGrowth RateStageAssociated SyndromesPerformance Status



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Limited StageStage I-IIA

Mediastinal Staging, SurgeryN0: Adjuvant ChemotherapyN1-2: CTRTMedically inoperable: SABR

IIB-IIIBPS0-2: Concurrent CTRTPS3-4: CT +/- RT

Extensive StageManage Syndromes and Local symptomsBrain Mets: WBRTFirst Line Chemotherapy

Platinum + EtoposidePCI to responders

Second Line TherapyTopotecanNivolumab +/- IpilimumabPembrolizumab

Small Cell Neuroendocrine Carcinoma

=


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Kujtan; Journal of Thoracic Oncology, May 2018

Large Cell Neuroendocrine Carcinoma

Stage IAHR 0.63p=0.018

Stage IBHR 0.55p=0.001


• Less Sensitive to cytotoxic chemotherapy than Small Cell NEC

• Evidence that NSCLC chemotherapy (Gem/Cis, Gem/Tax)is more effective than Etoposide / Platinum

• Low Rb1 IHC expression may predict chemo-sensitivity

• There is a role for adjuvant chemotherapy in LC NEC


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Signaling Pathways in NETs

Dong, Clin Cancer Res 2012


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• mTOR expression high in pulmonary NETs and associated with more advanced disease

• Autocrine stimulation of mTOR pathway by IGF1

• TSC1 is a regulator of mTOR pathway activation

• Mutations in mTOR and TSC1 occur in TC/AC, but not in LCNEC or SCLC

• mTOR pathway activation associated with response to Everolimus

Targeting mTOR in Pulmonary Carcinoid Tumours


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Targeting m-TOR

RADIANT 4: Non-Functional NETsEverolimus vs Placebo

PFS

OS

HR 0.39P<0.00001

HR 0.64P=0.037

G1/G2 Advanced NET GI/Lung

Randomized, Placebo-Controlled DB Phase III



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Targeting m-TOR

RADIANT 4: Non-Functional NETsEverolimus vs Placebo

PFS

OS

HR 0.39P<0.00001

HR 0.64P=0.037

Yao, 2016Denis Talbot ESO 2018


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Radionuclide Imaging and Therapeutics


Components• 68Gallium = Radionuclide• DOTATATE = Chelator for 68Ga• Tyr3 octreotate = binds to SSR

68Ga-DOTATATE

PRRT


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PRRT in SSTR + Midgut NETs

Strosberg, 2017

NETTER-1: Randomized trial of lutetium-177 (177Lu)–Dotatate in patients with with advanced, progressive disease



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Long-term results of PRRT:Pulmonary NETs

ResponseN (%)

OverallN=114

177LuN=48

90YN=45

177Lu + 90YN=21

P Value

Stable Disease 46 (41) 22 (46) 16 (36) 8 (38)

Minor Response 15 (13) 8 (17) 4 (9) 3 (14)

Partial Response 15 (13) 6 (12) 4 (9) 5 (24) 0.3

Objective Response

30 (27) 14 (29) 8 (18) 8 (38) 0.2

Disease Control 76 (67) 36 (75) 24 (55) 16 (76) 0.08

Retrospective analysis: Manniello, Eur J Nucl Mol Imaging (2016)



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Lung NETsManagement Algorithm

Oxford NET Centre Algorithm, 2017

Everolimus Strep/Cape

Follow up Guidance


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Horizon Scanning: New Targets

• DNA Damage Repair

• Chromatin Remodeling

• Telomere Maintenance

• Delta-Like Ligand 3

• Immuno-therapeutics



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Whole Genome Sequencing


DNA Damage Repair

Chromatin Remodeling

Telomere Maintenance

Activation of mTOR Signaling

Scarpa, Nature (2017)


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European Neuroendocrine Tumor Society


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Take Home Messages


Incidence of Pulmonary carcinoids is increasing rapidly

Management of Associated syndromes is an important part of patient care

Complete surgical resection is the goal in managing early stage disease

Follow up after resection should be extended compared to NSCLC

68Ga DOTA PET imaging important in determining treatment Surgery/PRRT

Targeted therapy with mTORinhibitors for advanced stage

Carcinoid Tumours

Pt-based cytotoxic chemotherapy indicated for LCNEC and SCLC

Multi-Disciplinary team-work is the key to success


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Thank You


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